WO2000039104A1 - Composes phenazine, methodes et compositions pharmaceutiques permettant d'inhiber la poly(adp-ribose) polymerase (parp) - Google Patents

Composes phenazine, methodes et compositions pharmaceutiques permettant d'inhiber la poly(adp-ribose) polymerase (parp) Download PDF

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WO2000039104A1
WO2000039104A1 PCT/US1999/030979 US9930979W WO0039104A1 WO 2000039104 A1 WO2000039104 A1 WO 2000039104A1 US 9930979 W US9930979 W US 9930979W WO 0039104 A1 WO0039104 A1 WO 0039104A1
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cancer
straight
branched chain
disease
diseases
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PCT/US1999/030979
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WO2000039104A9 (fr
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Jie Zhang
Kevin Leonard Tays
Jia-He Li
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Guilford Pharmaceuticals, Inc.
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Priority to AU22174/00A priority Critical patent/AU2217400A/en
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Publication of WO2000039104A9 publication Critical patent/WO2000039104A9/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/46—Phenazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to inhibitors of the nucleic enzyme poly(adenos ⁇ ne 5'- dip ospho- ⁇ bose) polymerase ["poly(ADP- ⁇ bose) polymerase” or "PARP”, which is also sometimes called “PARS” for poly(ADP- ⁇ bose) synthetase or "PART” for poly(ADP- 5 ribose) transferasej.
  • the invention relates to the use of PARP inhibitors to prevent and/or treat tissue damage resulting from cell damage or death due to necrosis or apoptosis, neural tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases; to prevent or treat vascular stroke, to treat or prevent cardiovascular disorders; to treat other conditions and/or disorders such 0 as age-related macular degeneration, HIN, AIDS and other immune diseases, arthritis, atherosclerosis, cachexia, cancer, degenerative diseases of skeletal muscle involving replicative senescence, diabetes, head trauma, immune senescence, inflammation, inflammatory bowel disorders (such as colitis and Crohn's disease), muscular dystrophy, osteoarth ⁇ tis.
  • osteoporosis chronic and acute pain (such as neuropathic pain), renal failure, retinal ischemia, septic shock (such as endotoxic shock), and skin agmg, to extend the lifespan and proliferative capacity of cells; to alter gene expression of senescent cells; or to radiosensitize hypoxic tumor cells.
  • PARP Poly(ADP- ⁇ bose) polymerase
  • PARP Poly(ADP-R ⁇ bose) Polymerase at Human Telomeres
  • These structurally-variant forms of PARP enzymes are all referred to herein as PARP.
  • the compounds of the present inventicn would be expected to inhibit the PARP activity of any and all enzymes which can perform ADP-Ribosylation .
  • PARP enzymes collectively referred to as PARP, play a physiological role in the repair of strand breaks in DNA. Once activated by damaged DNA fragments, PARP catalyzes the attachment: of up to 100 ADP-ribose units to a variety of nuclear proteins, including histones and PARP itself. While the exact range of functions of PARP has not been fully established, this enzyme is thought to play a role in enhancing DNA repair.
  • PARP activation has also been shown to provide an index of damage following neurotoxic insults by glutamate (via NMDA receptor stimulation), reactive oxygen intermediates, amyloid ⁇ -protein, n-methyi-4 -phenyl-1, 2 , 3 , 6-tetrahydropyridine (MPTP) and its active metabolite N-methyl-4 -phenylpyridine (MPP ⁇ ) , which participate in pathological conditions such as stroke, Alzheimer's disease and Parkinson's disease.
  • MPTP 6-tetrahydropyridine
  • MPP ⁇ N-methyl-4 -phenylpyridine
  • NMDA N-methyl-D-aspartate
  • Glutamate serves as the predominate excitatory neurotransmitter in the central nervous system (CNS) . Neurons release glutamate in great quantities when they are deprived of oxygen, as may occur during an ischemic brain insult such as a stroke or heart attack. This excess release of glutamate in turn causes over-stimulation
  • N-methyl-D-aspartate NMDA
  • AMPA N-methyl-D-aspartate
  • Kainate MGR receptors.
  • glutamate binds to these receptors, ion channels in the receptors open, permitting flows of ions across their cell membranes, e.g., Ca 2+ and Na + into the cells and K + out of the cells.
  • These flows of ions especially the influx of Ca 2+ , cause overstimulation of the neurons.
  • the over-stimulated neurons secrete more glutamate, creating a feedback loop or domino effect which ultimately results in cell damage or death via the production of proteases, upases and free radicals .
  • NMDA receptors activate neuronal nitric oxide synthase (NNOS) , which causes the formation of nitric oxide (NO) , which more directly mediates neurotoxicity. Protection against glutamate neurotoxicity mediated through the NMDA receptors has occurred following treatment with NOS inhibitors. See Dawson et al . , "Nitric Oxide Mediates Glutamate Neurotoxicity in Primary Cortical Cultures", Proc . Na tl . Acad. Sci . USA, 89:6363-71 (1991) ; and Dawson et al . , “Mechanisms of Nitric Oxide-mediated Neurotoxicity in Primary Brain Cultures", J. Neurosci .
  • Zhang et al . U.S. Patent No. 5,587,384 issued December 24, 1996, discusses the use of certain PARP inhibitors, such as benzamide and 1 , 5-dihydroxy-isoquinoline , to prevent NMDA- mediated neurotoxicity and, thus, treat stroke, Alzheimer's disease, -Parkinson's disease and Huntington ' s disease.
  • certain PARP inhibitors such as benzamide and 1 , 5-dihydroxy-isoquinoline
  • Zhang et al . may have been in error in classifying neurotoxicity as NMDA- mediated neurotoxicity. Rather, the in vivo neurotoxicity present is more appropriately classified as glutamate neurotoxicity. See Zhang et al .
  • PARP inhibitors have been reported to be effective in radiosensitizing hypoxic tumor cells and effective in preventing tumor cells from recovering from potentially lethal damage of DNA after radiation therapy, presumably by their ability to prevent DNA repair. See U.S. Patent Nos. 5,032,617; 5,215,738; and 5 , 041 , 653.
  • Colitis was induced in rats by intraluminal administration of the hapten trinitrobenzene suifonic acid in 50% ethanoi and treated with 3 -aminobenzamide, a specific inhibitor of PARP activity. Inhibition of PARP activity reduced the inflammatory response and restored the morphology and the energetic status of the distal colon. See also,
  • nicotinamide may be related to inhibition of the NO-mediated activation of the energy-consuming DNA repair cycle, triggered by poly(ADP ribose) synthetase. See also, Cuzzocrea, "Role of Peroxynitrite and Activation of Poly (ADP-Ribose) Synthetase in the Vascular Failure Induced by Zymosan-activated Plasma, " Brit. J. Pharm . , 122:493-503 (1997).
  • PARP inhibitors are used for peripheral nerve injuries, and the resultant pathological pain syndrome known as neuropathic pain, such as that induced by chronic constriction injury (CCI) of the common sciatic nerve and in which transsynaptic alteration of spinal cord dorsal horn characterized by hyperchromatosis of cytoplasm and nucleoplasm (so-called "dark” neurons) occurs.
  • CCI chronic constriction injury
  • nucleoplasm cytoplasm and nucleoplasm
  • PARP inhibitors have also been used to extend the lifespan and proliferative capacity of cells including treatment of diseases such as skin aging, Alzheimer's disease, atherosclerosis, osteoarthritis , osteoporosis, muscular dystrophy, degenerative diseases of skeletal muscle involving replicative senescence, age-related macular degeneration, immune senescence, AIDS, and other immune diseases; and to alter gene expression of senescent cells. See WO 98/27975.
  • phenazme compounds can inhibit PARP activity
  • These compounds can treat or prevent tissue damage resulting from cell damage or death due to necrosis or apoptosis and/or can ameliorate neural tissue damage, including that following focal ischemia and reperfusion I ⁇ JUI
  • the present invention relates to novel poly(ADP-nbose) polymerase (“PARP”) inhibitors, compositions containing the same, and methods for using the same Specifically, the present invention relates to a compound of formula I
  • R1.-R9 and Z are independently hydrogen, hydroxy, halo, haloalkyl, thiocarbonyl , cyano, nitro, amino, imino, alkyiamino, aminoalkyl, sulfhydryl, thioalkyl, alkylthio, sulfonyl, alkylsulfonyl, C_ - C 9 straight or branched chain alkyl, C-C 6 straight or branched chain alkenyl, C : -C 9 straight or branched chain alkynyl, C x -C 6 straight or branched chain alkoxy, C ; -C 6 straight or branched chain alkenoxy, C 2 -C ⁇ straight or branched chain alkynoxy, aryl, carbocycle, heterocycle, aralkyi, alkylaryl, alkylaryloxy, aryioxy, aralkyloxy, aralkylsulfonyl ,
  • U is C or N, and R and R ⁇ are defined above; and X and Y are independently aryl, carbocycle, or heterocycle; wherein said alkyl, alkenyl, alkynyl, imino, aryl, carbocycle, heterocycle, aralkyi, alkylaryl, alkylaryloxy, aryioxy, aralkyloxy, aralkylsulfonyl, aralkylamino, arylamino, arylazo, arylthio, aralkylthio of X, Y, or Z is optionally substituted with one or more substituents selected from hydroxy, halo, haloalkyl, haloalkyiamide, thiocarbonyl, double-bonded oxygen to form carbonyl , carboxy, alkoxy, alkenoxy, cyano, nitro, amino, imino, amide, -NHCOR ?
  • R_ is defined above, C : -C straight or branched chain alkyl, C ; -C_ straight or branched chain alkenyl or alkynyl, alkyiamino, aminoalkyl, sulfhydryl, thioalkyl, alkylthio, sulfonyl, aryl, aralkyi, aryioxy, arylamino, arylazo, arylthio, carbocycle, or heterocycle.
  • a preferred embodiment of this invention is the compound of 'formula I, where X is a substituted or unsubstituted phenyl .
  • Y is an aryl substituted with at least one non-hydrogen, non-interfering substituent, more preferably where the substituent is hydroxy, amino, nitro, sulfhydryl, halo, alkyiamino, carboxy, or alkoxy, and most preferably where the substituent is at the ortho position of said aryl relative to said azo group of formula I bound to said aryl.
  • Y is 1-naphthyl, (2-hydroxy)-l-naphthyl. (2- ammo)-l-naphthyl. (2-sulfhydryl)- 1-naphthyl, phenyl, 2-hydroxy-phenyl, 2-ammo-phenyl, or 2-sulfhydryl-phenyl
  • R ⁇ -R 6 are independently hydrogen, hydroxy, halo, amino. nitro, lower-alkyl, lower-alkenyl, lower-alkynyl, carboxy, alkoxy. or alkenoxy
  • Rj and R 4 are each methyl
  • R 2 , R 3 , R 5 , and R 6 are each hydrogen
  • Z is aryl or aralkyi, which may be substituted in any position with at least one non-hydrogen, non-mterfenng substituent such as hydroxy, amino, imino, nitro, amide, urea, haloalkylamide. double- bonded oxygen to form carbonyl, sulfhydryl. halo, alkyiamino, alkoxyimine, carboxy, or alkoxy
  • the present invention further relates to a pharmaceutical composition comp ⁇ sing a pharmaceutically acceptable earner and a compound of formula (I)
  • R R 9 and Z are independently hydrogen, hydroxy, halo, haloalkyl, thiocarbonyl, cyano, nitro, amino, imino, alkyiamino, aminoalkyl, sulfhydryl, thioalkyl, alkylthio, sulfonyl, alkylsulfonyl, C ⁇ -C straight or branched chain alkyl, C -C 9 straight or branched chain alkenyl, C 2 -C straight or branched chain alkynyl.
  • U is C or N, and R and R 8 are defined above; and X and Y are independently aryl, carbocycle, or heterocycle; wherein said alkyl, alkenyl, alkynyl. imino, aryl, carbocycle. heterocycle, aralkyi, alkylaryl, alkylaryloxy, aryioxy, aralkyloxy, aralkylsulfonyl. aralkylamino, arylamino, arylazo, arylthio, aralkylthio of Ri-Rg, X.
  • Y, or Z is optionally substituted with one or more substituents selected from hydroxy, halo, haloalkyl, haloalkylanude, thiocarbonyl, double-bonded oxygen to form carbonyl, carboxy, alkoxy. alkenoxy. cyano, nitro, amino, imino, amide. -NHCOR9 or -COOR 9 where R 9 is defined above. -C ⁇ straight or branched chain alkyl, C -C 6 straight or branched chain alkenyl or alkynyl, alkyiamino, aminoalkyl, sulfhydryl. thioalkyl, alkylthio, sulfonyl, aryl, aralkyi, aryioxy, arylamino, arylazo, arylthio, carbocycle, or heterocycle.
  • the present invention further relates to a method of inhibiting PARP activity, treating or preventing diseases or disorders, alternativeng gene expression, or radiosensiUzing, comprising: administenng a therapeutically effective amount of a compound of formula I:
  • R ⁇ -R 9 and Z are independently hydrogen, hydroxy, halo, haloalkyl, thiocarbonyl, cyano, nitro, amino, imino, alkyiamino, aminoalkyl, sulfhydryl, thioalkyl, alkylthio, sulfonyl, alkylsulfonyl, C 1 -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 2 -C 9 straight or Drancned chain alxynyl, C_-C straignt or branched chain alkoxy, C_-C b straight or branched chain a! ⁇ enoxy, C 2 -C 6 straight or branched chain alkynoxy, aryl, carbocycle, heterocycle
  • U is C or N, and RT and R 9 are defined acove ; and X and Y are independently aryl, carbocycle, or heterocycle; wherein said alkyl, alkenyl, alkynyl, immo, aryl, carbocycle, heterocycle, aralkyi, alkylaryl, alkylaryloxy, aryioxy, aralkyloxy, aralkylsulfonyl, aralkylamino, arylamino, arylazo, arylthio, aralkylthio of R J -R B , X, Y, or Z is optionally substituted with one or more substituents selected from hydroxy, halo, haloalkyl, naloalkylamide , thiocarbonyl, double-bonded oxygen to form carbonyl, carboxy, alkoxy, alkenoxy, cyano, nitro, ammo, immo, amide, -NHCOR
  • Figure 1 is a graph showing the distribution of the cross-sectional infarct area at representative levels along the rostrocaudal axis, as measured from the teraural line non-treated animals and m animals treated with 10 mg/kg of 3,4 j d ⁇ hydro-5- [4- (l-piperidmyl) -botoxyl] -1 (2H) - lsoqumolmone .
  • Figure 2 shows the effect of traperitoneal administration of 3 , 4-d ⁇ hydro-5- [4- (1-p ⁇ per ⁇ dmyl) -butoxy] - 1 (2H) -lsoqumolmone on the infarct volume.
  • the present invention pertains to compounds, pharmaceutical compositions containing the same, methods of using the same, and process of making the same, wherein such compounds are useful as inhibitors of poly(ADP-nbose) polymerase (PARP).
  • PARP poly(ADP-nbose) polymerase
  • they may treat or prevent neural tissue damage resulting from cell damage or death due to necrosis or apoptosis, cerebral ischemia and reperfusion injury or neurodegenerative diseases in an animal; they may extend the lifespan and proliferative capacity of cells and thus be used to treat or prevent diseases associated therewith; they may alter gene expression of senescent cells; and they may radiosensitize hypoxic tumor cells.
  • the compounds of the invention treat or prevent tissue damage resulting from cell damage or death due to necrosis or apoptosis. and/or effect neuronal activity, either mediated or not mediated by glutamate neurotoxicity These compounds are thought to interfere with more than the glutamate neurotoxicity and NO-mediated biological pathways. Further, the compounds of the invention can treat or prevent other tissue damage related to PARP activation
  • the compounds of the invention can treat or prevent cardiovascular tissue damage resulting from cardiac ischemia or reperfusion injury
  • Reperfusion injury for instance, occurs at the termination of cardiac bypass procedures or dunng cardiac arrest when the heart, once prevented from receiving blood, begins to reperfuse.
  • the compounds of the present invention can also be used to extend or increase the lifespan or proliferation of cells and thus to treat or prevent diseases associated therewith and induced or exacerbated by cellular senescence including skin ag g, atherosclerosis, osteoarthntis, osteoporosis, muscular dystrophy, degenerative diseases of skeletal muscle involving rep cative senescence, age-related macular degeneration, immune senescence, HIN, AIDS and other immune diseases, immune senescence, and other diseases associated with cellular senescence and ag g, as well as to alter the gene expression of senescent cells, and inflammation, such as inflammatory bowel disorders (such as colitis and Crohn's disease),.
  • diseases associated therewith and induced or exacerbated by cellular senescence including skin ag g, atherosclerosis, osteoarthntis, osteoporosis, muscular dystrophy, degenerative diseases of skeletal muscle involving rep cative senescence, age-related macular degeneration, immune
  • the compounds of the present invention can be used to prevent or treat vascular stroke; to treat or prevent cardiovascular disorders; to treat other conditions and/or disorders such as age-related macular degeneration, AIDS and other immune diseases, arthritis, atherosclerosis, cachexia, cancer, degenerative diseases of skeletal muscle involving replicative senescence, diabetes, head trauma, immune senescence, inflammatory bowel disorders (such as colitis and Crohn's disease), muscular dystrophy, cstecarthriti ⁇ , osteoporosis, chronic and/cr acute pain (such as neuropathic pain), renal failure, retinal ischemia, septic shock (such as endotoxic shock), and skin aging.
  • the compounds of the invention act as PARP inhibitors to treat or prevent tissue damage resulting from ceil death or damage due to necrosis or apoptosis; to treat or prevent neural tissue damage resulting from cerebral ischemia and reperfusion injury or neurodegenerative diseases in an animal; to extend and increase the lifespan and proliferative capacity of cells; to alter gene expression of senescent cells; and to radiosensitize tumor cells.
  • the phenazine compounds of the present invention can act to inhibit PART and can ameliorate neural tissue damage and cardiovascular tissue damage, including that following focal ischemia, myocardial infarction, and reperfusion injury.
  • inhibition of PARP activity spares the cell from energy loss, preventing irreversible depolarization of the neurons and, thus, provides neuroprotection.
  • PARP activation may play a common role in still other excitotoxic mechanisms, perhaps as yet undiscovered, in addition to the production of free radicals and NO.
  • the compounds of the invention exhibit an IC 50 for inhibiting PARP in vitro of about 100 ⁇ M or lower, more preferably, about 25 ⁇ M or lower, most preferably, about 1 ⁇ M or lower.
  • Preferred PARP inhibitors of the present invention include compounds having formula I
  • R 1 -R 9 and Z are independently hydrogen, hydroxy, halo, haloalkyl. thiocarbonyl, cyano, nitro, amino, imino, alkyiamino. aminoalkyl, sulfhydryl. thioalkyl. alkylthio. sulfonyl, alkylsulfonyl, -C straight or branched chain alkyl, C 2 -C straight or branched chain alkenyl, C 2 -C 9 straight or branched chain alkynyl.
  • U is C or N, and R and Rg are defined above; and X and Y are independently aryl, carbocycle, or heterocycle, wherein said alkyl, alkenyl, alkynyl, immo, aryl, carbocycle, heterocycle, aralkyi, alkylaryl, alkylaryloxy, aryioxy, aralkyloxy, aralkylsulfonyl, aralkylamino, arylamino, arylazo, arylthio, aralkylthio of R ⁇ -R 8 , X, Y, or Z is optionally substituted with one or more substituents selected from hydroxy.
  • a preferred embodiment of this invention is the compound of formula I, where X is a substituted or unsubstituted phenyl .
  • Y is an aryl substituted with at least one non-hydrogen, non-interf ring substituent, more preferably where the substituent is hydroxy, amino, nitro, sulfhydryl, halo, alkyiamino, carboxy, or alkoxy, and most preferably where the substituent is at the ortho position of said aryl relative to said azo group of formula I bound to said aryl .
  • Y is 1-naphthyl, [ 2 -hydroxy) -1-naphthyi , (2-aminc)- i-naphthyl, ( 2 -sulfhydryl) - 1-naphthyi , phenyl, 2-hydroxy- phenyl, 2-amino-phenyl , or 2 -sulfhydryl -phenyl .
  • R- . -R. . are independently hydrogen, hydroxy, halo, amino, nitro, lower- alkyl, lower-alkenyl, lower-alkynyl, carboxy, alkoxy, or alkenoxy.
  • R_ and R ⁇ are each methyl, and R 2 , R 3 , R 5/ and R 5 are each hydrogen.
  • Z is aryl or aralkyi, which may be substituted in any position with at least one non-hydrogen, non-interfering substituent such as hydroxy, amino, imino, nitro, amide, urea, haloalkylamide, double-bonded oxygen to form carbonyl, sulfhydryl, halo, alkyiamino, alkoxyimine, carboxy, or alkoxy.
  • a pharmaceutical composition which comprises (i) a therapeutically effective amount of the compound of formula I; and (ii) a pharmaceutically acceptable carrier.
  • alkyl means a branched or unbranched saturated hydrocarbon chain comprising a designated number of carbon atoms.
  • C ! -C 6 straight or branched alkyl hydrocarbon chain contains 1 to 6 carbon atoms, and includes but is not limited to substituents such as methyl, ethyl, propyl , iso-propyl, butyl, iso-butyl, tert -butyl, n-pentyi, n- hexyl , and the like, unless otherwise indicated.
  • Alkenyl means a branched or unbranched unsaturated hydrocarbon chain comprising a designated number of carbon atoms.
  • C 2 -C 3 straight or branched alkenyl hydrocarbon chain contains 2 to 6 carbon atoms having at least one double bond, and includes but is not limited to substituents such as ethenyi , propenyl , isopropenyl, butenyl, iso-butenyl, tert -butenyl , n-pentenyi, n-hexenyl, and the like, unless otherwise indicated.
  • alkynyl refers to a hydrocarbon chain containing a carbon-carbon triple bond.
  • alkynyl groups include, but are not limited to 1-butyne, 2-butyne, 2-pentyne, 3 -methyl -1-butyne .
  • Alkoxy means the group -OR wherein R is alkyl as herein defined.
  • R is a branched or unbranched saturated hydrocarbon chain containing 1 to 6 carbon atoms.
  • Cyclo used herein as a prefix, refers to a structure characterized by a closed ring.
  • Hale means at least one fluoro, chloro, bromc, or iodo moiety, unless otherwise indicated.
  • Amino compounds include amine (NH 2 ) as well as substituted amino groups comprising alkyls of one through six carbons .
  • Ar and “Aryl” as used herein refers to an aryl or heteroaryl moiety which is substituted or unsubstituted, especially a cyclic or fused cyclic ring and includes a mono-, bi-, or tricyclic, alicylcic, carbocyclic or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one or more position (s) with halo, haloalkyl, hydroxyl, nitro, trifluoromethyl , C : -C 0 straight or branched chain alkyl,
  • heterocyclic ring contains 1-4 heteroatom (s) selected from the group consisting of 0, N, or S; wherein aromatic or tertiary alkyl amines are optionally oxidized to a corresponding N-oxide.
  • aryl or heteroaryl moieties include but are not limited to phenyl, benzyl, naphthyl, pyrrolyl , pyrrolidinyl , pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinoiinyl , furyl , tetrahydrofuryl , thiophenyl , imidazolyl, imidazolinyl, triazinyl, morpholinyl, thiomorpholinyl, oxazolyl, isoxazolyl, triazolyl, tetrahydrothienyl , benzopyranyl , benzofuranyl , benzothienyl, indolyl, indoiinyl, indolizinyl, cinnolinyl, phthalazinyl , quinazolinyl , quinoxalinyl , pteridinyl, quin
  • Alkyi refers to an aryl group that is joined to a structure by one or more alkyl groups, e.g., benzyl, phenethyi, and the like.
  • alkylaryl refers to an alkyl group that is joined to a structure by one or more aryl groups; and
  • aryioxy refers to an aryl group that is joined to a structure by an oxygen group.
  • arylamino refers to an aryl group that is joined to a structure by an amino group
  • arylaikyloxy refers to an aryl group that is joined to a structure by an aikyloxy group, where the last named component, oxygen, is directly joined to the structure .
  • Phenyl includes ail possible isomeric phenyl radicals, optionally monosubstituted or multi-substituted with substituents selected from the group consisting of amino, trifiuoromethyl , C_-C 6 straight or branched chain alkyl, C z - C s straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkyiamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, hydroxy, halo, haloalkyl, NR 2 wherein R 2 is selected from the group consisting of hydrogen, ( C_- C 6 ) -straight or branched chain alkyl, (C 3 -C 3 ) straight or branched chain alkenyl or alkynyl, and (C ⁇ C,,) bri
  • Carbocycle refers to a cyclic carbon ring structure, which may be saturated or unsaturated, and may also be bridged or unbridged.
  • carbocycle moieties include, but are not limited to, cyciohexyl, cyclopentyl, cycloheptyl, cyclooctyi, adamantyl , and bicyclopentyi .
  • the compounds of the present invention possess one or more asymmetric center (s) and thus can be produced as mixtures
  • stereoisomers (racemic and non-racemic) of stereoisomers, or as individual enantiomers or diastereomers .
  • the individual stereoisomers may be obtained by using an optically active starting material, by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolution of the compound of formula (I) . It is understood that the individual stereoisomers as well as mixtures (racemic and non-racemic) of stereoisomers are encompassed by the scope of the present invention.
  • the S-stereoisomer at atom i of formula I is most preferred due to its greater activity.
  • “Isomers” are different compounds that have the same molecular formula and includes cyclic isomers such as (iso) indole and other isomeric forms of cyclic moieties.
  • “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space.
  • “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other.
  • “Diastereoisomers are stereoisomers which are not mirror images of each other.
  • “Racemic mixture” means a mixture containing equal parts of individual enantiomers.
  • “Non-racemic mixture” is a mixture containing unequal parts of individual enantiomers or stereoisomers .
  • the compounds of the invention may be useful in a free base form, in the form of pharmaceutically acceptable salts, pharmaceutically acceptable hydrates, pharmaceutically acceptable esters, pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs , pharmaceutically acceptable metabclites, and in the form of pharmaceutically acceptable stereoisomers. These forms are all within the scope of the invention. In practice, the use of these forms amounts to use of the neutral compound.
  • “Pharmaceutically acceptable salt”, “hydrate”, “ester” or “solvate” refers to a salt, hydrate, ester, or solvate of the inventive compounds which possesses the desired pharmacological activity and which is neither biologically nor otherwise undesirable.
  • Organic acids can be used to produce salts, hydrates, esters, or solvates such as acetate, adipate, alginate, aspartate, benzoate , benzenesulfonate , p- toluenesulfonate, bisulfate, sulfamate, sulfate, naphthyiate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane- propionate, digluconate, dodecyisulfate , ethanesulfonate , fumarate, gluccheptanoate , giycerophosphate , hemisulfate heptanoate, he
  • Suitable base salts, hydrates, esters, or solvates include hydroxides, carbonates, and bicarbonates of ammonia, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, and z c salts.
  • Salts, hydrates, esters, or solvates may also be formed with organic bases.
  • Organic bases suitable for the formation of pharmaceutically acceptable base addition salts, hydrates, esters, or solvates of the compounds of the present invention include those that are non- oxic and strong enough to form such salts, hydrates, esters, or solvates.
  • the class of such organic bases may include mono-, di-, and trialkylamines, such as methylamine, dimethylamine, triethylamine and dicyclohexylamine ; mono-, di- or trihydroxyalkylamines , such as mono-, di-, and triethanolamine; amino acids, such as arginine and lysine; guanidine;- N-methyl-glucosamine ; N-methyl-glucamine ; L- glutamine; N-methyi-piperazine ; moroholine ; ethylenediamine; N-benzyl-phenethylamine; (trihydroxy-methyl) aminoethane ; and the like.
  • mono-, di-, and trialkylamines such as methylamine, dimethylamine, triethylamine and dicyclohexylamine
  • mono-, di- or trihydroxyalkylamines such as mono-, di-, and triethanolamine
  • amino acids such as arginine and lys
  • basic nitrogen- containing groups can be quaternized with agents including: lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyi , lauryi, myristyl and stearyl chlorides, bromides and iodides; and aralkyi halides such as benzyl and phenethyl bromides .
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such as decyi , lauryi, myristy
  • the acid addition salts, hydrates, esters, or solvates of the basic compounds may be prepared either by dissolving the free base of a PARP inhibitor in an aqueous or an aqueous alcohol solution or ether suitable solvent containing the appropriate acid or base, and isolating the salt by evaporating the solution.
  • the free base of the PARP inhibitor may be reacted with an acid, as well as reacting the PARP inhibitor having an acid group thereon with a base, such that the reactions are in an organic solvent, in which case the salt separates directly or can be obtained by concentrating the solution.
  • “Pharmaceutically acceptable pro rug” refers to a derivative of the inventive compounds which undergoes biotransformation prior to exhibiting its pharmacological effect (s) .
  • the prodrug is formulated with the objective (s) of improved chemical stability, improved patient acceptance and compliance, improved b cavailability, prolonged duration of action, improved organ selectivity, improved formulation
  • the prodrug can be readily prepared from the inventive compounds using methods known in the art, such as those described by Burger ' s Medicinal Chemistry and Drug Chemistry, Fifth Ed., Vol. 1, pp. 172-178, 949-982
  • inventive compounds can be transformed into prodrugs by converting one or mere of the hydroxy or carboxy groups into esters.
  • “Pharmaceutically acceptable metabolite” refers to drugs that have undergone a metabolic transformation. After entry into the body, most drugs are substrates for chemical reactions that may change their physical properties and biologic effects. These metabolic conversions, which usually affect the polarity of the compound, alter the way m which drugs are distributed in and excreted from the body. However, in some cases, metabolism of a drug is required for therapeutic effect. For example, anticancer drugs of the antimetabolite class must be converted to their active forms after they have been transported into a cancer cell. Since must drugs undergo metabolic transformation of some kind, the biochemical reactions that play a role in drug metabolism may be numerous and diverse. The main site of drug metabolism is the liver, although other tissues may also participate.
  • a feature characteristic of many of these transformations is that the metabolic products are more polar than the parent drugs, although a polar drug does sometimes yield a less polar product.
  • Substances with high iipid/water partition coefficients which pass easily across membranes, also diffuse back readily from tubular urine through the renal tubular cells into the plasma. Thus, such substances tend to have a low renal clearance and a long persistence in the body. If a drug is metabolized to a more polar compound, one with a lower partition coefficient, its tubular reabsorption will be greatly reduced.
  • the specific secretory mechanisms for anions and cations in the proximal renal tubules and in the parenchyma! liver cells operate upon highly polar substances .
  • phenacetin acetophenetidin
  • acetanilide is both mild analgesic and antipyretic agents, but are each transformed within the body to a more polar and more effective metabolite, p -hydroxyacetanilid (acetaminophen) , which is widely used today.
  • p -hydroxyacetanilid acetaminophen
  • the principal plasma component is a further metabolite, that is inert and can be excreted from the body.
  • the plasma concentrations of one or more metabolites, as well as the drug itself, can be pharmacologically important.
  • Phase I or functionalization reactions generally consist of (1) oxidative and reductive reactions that alter and create new functional groups and (2) hydrolytic reactions that cleave esters and amides to release masked functional groups. These changes are usually m the direction of increased polarity.
  • Phase II reactions are conjugation reactions which the drug, or often a metabolite of the drug, is coupled to an endogenous substrate, such as giucuronic acid, acetic acid, or sulfuric acid.
  • Oxidative deammation (monoamine oxidase and diamme oxidase)
  • the compounds of tne present invention exhibit pharmacological activity and are, therefore, useful as pharmaceuticals.
  • the compounds exhibit central nervous and cardiac vesicular system activity.
  • tautome ⁇ c forms when possible, are included in the invention.
  • the tautomeric forms of the following compounds are exemplary:
  • the novel compounds of the invention will have an IC S0 for inhibiting poly (ADP-ribose) synthetase in vi tro of 100 ⁇ M or lower, preferably 50 uM or lower, more preferably 30 ⁇ M or lower, more preferably 10 ⁇ M er lower, and most preferably 40 nM or lower.
  • R can be any possible substituent as described herein, including:
  • the phenazine compounds of the present invention can treat or prevent tissue damage resulting from cell damage or death due to necrosis or apoptosis; can ameliorate neural or cardiovascular tissue damage, including that following focal ischemia, myocardial infarction, and reperfusion injury; can treat various diseases and conditions caused or exacerbated by PARP activity; can extend cr increase the lifespan or proliferative capacity of ceils; can alter the gene expression of senescent cells; and can radiosensitize cells.
  • inhibition of PARP activity spares the cells from energy loss, preventing irreversible depolarization of the neurons, and thus, provides neuroprotectien. While not being bound to any one particular theory, it is thought that PARP activation may play a common role in still other excitotoxic mechanisms, perhaps as yet undiscovered, in addition to the production of free radicals and NO.
  • the present invention further relates to a method of administering a therapeutically effective amount of the above-identified compounds in an amount sufficient to inhibit PAR? activity, to treat cr prevent tissue damage resulting from cell damage or death due to necrosis or apoptosis, to effect a neuronal activity not mediated by glutamate neurotoxicity, to effect a neuronal activity mediated by glutamate neurotoxicity, to treat neural tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases; to prevent or treat vascular stroke; to treat or prevent cardiovascular disorders; to treat other conditions and/or disorders such as age-related macular degeneration, AIDS and other immune diseases, arthritis, atherosclerosis, cachexia, cancer, degenerative diseases of skeletal muscle involving replicative senescence, diabetes, head trauma, immune senescence, inflammatory bowel disorders (such as colitis and Crohn's disease), muscular dystrophy, osteoarthritis , osteoporosis, chronic and/cr acute pain (such as neur
  • the present invention relates to a method of treating, preventing or inhibiting a neurological disorder in an animal, which comprises administering to said animal a therapeutically effective amount of the above- identified compounds.
  • the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, traumatic brain injury, physical damage to the spinal cord, stroke associated with brain damage, focal ischemia, global ischemia, reperfusion injury, demyeiinating disease and neurcicgical disorder relating to neurodegeneration.
  • the reperfusion injury is a vascular stroke.
  • the peripheral neuropathy is caused by Guillain-Barre syndrome.
  • the demyeiinating disease is multiple sclerosis.
  • the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.
  • Yet another preferred embodiment is a method of treating, preventing , or inhibiting a cardiovascular disease in an animal, such as angina pectoris, myocardial infarction, cardiovascular ischemia, and cardiovascular tissue damage related to PARP activation, by administering to said animal an effective amount of the compounds of the present invention.
  • the present invention also contemplates the use of compound of Formula I for inhibiting PARP activity; and/or for treating, preventing or inhibiting tissue damage resulting from cell damage or death due to necrosis or apoptosis,- and/or for treating, preventing or inhibiting a neurological ⁇ isorder in an animal .
  • the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, traumatic brain injury, physical damage to the spinal cord, stroke associated with brain damage, focal ischemia, global ischemia, reperfusion injury, demyeiinating disease and neurological disorder relating to neurodegeneration.
  • Another preferred embodiment is when the reperfusion injury is a vascular stroke. Yet another preferred embodiment is when the peripheral neuropathy is caused by Guillain-Barre syndrome. Still another preferred embodiment is when the demyeiinating disease is multiple sclerosis. Another preferred embodiment is when the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis .
  • the present invention also contemplates the use of the compound of formula I in the preparation of a medicament for the treatment of any of the diseases and disorders in an animal described herein.
  • the disease or disorder is a neurological disorder.
  • the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, traumatic brain injury, physical damage to the spinal cord, stroke associated with brain damage, focal ischemia, global ischemia, reperfusion injury, demyeiinating disease and neurological disorder relating to neurodegeneration.
  • the reperfusion injury is a vascular stroke.
  • the peripheral neuropathy is caused by Guillain-Barre syndrome.
  • demyeiinating disease is multiple sclerosis.
  • the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.
  • preventing neurodegeneration includes the ability to prevent neurodegeneration in patients newly diagnosed as having a neurodegenerative disease, or at risk of developing a new degenerative disease and for preventing further neurodegeneration in patients who are already suffering from or have symptoms of a neurodegenerative disease .
  • treatment covers any treatment of a disease and/or condition in an animal, particularly a human, and includes:
  • neural tissue damage resulting from ischemia and reperfusion injury includes neurotoxicity, such as seen in vascular stroke and global and fecal ischemia.
  • neurotoxicity such as seen in vascular stroke and global and fecal ischemia.
  • neurodegenerative diseases includes Alzheimer's disease, Parkinson's disease and Huntington's disease.
  • ischemia relates to localized tissue anemia due to obstruction of the inflow of arterial biocd.
  • Global ischemia occurs under conditions in which blood flow to the entire brain ceases for a period of time, such as may result from cardiac arrest .
  • Focal ischemia occurs under conditions in which a portion of the brain is deprived of its normal blood supply, such as may result from thromboembolytic occlusion of a cerebral vessel, traumatic head injury, edema, and brain tumors .
  • cardiovascular disease relates to myocardial infarction, angina pectoris, vascular or myocardial ischemia, and related conditions as wouid be known by those of skill in the art which involve dysfunction of or tissue damage to the heart or vasculature, and especially, but not limited to, tissue damage related to PARP activation.
  • radiationosensitizer as used herein, is defined as a molecule, preferably a low molecular weight molecule, administered to animals in therapeutically effective amounts to increase the sensitivity of the cells to be radiosensitized to electromagnetic radiation and/or to promote the treatment of diseases which are treatable with electromagnetic radiation.
  • Electromagnetic radiation treatment of other diseases not listed herein are also contemplated by the present invention.
  • the terms "electromagnetic radiation” and “radiation” as used herein includes, but is not limited to, radiation having the wavelength of 10 ⁇ 2 ° to 10 ⁇ meters.
  • Preferred embodiments of the present invention employ the electromagnetic radiation of: gamma-radiation (10 " ⁇ ° to 10 " “ “ m) x-ray radiation (10 " "" to 10 "?
  • ultraviolet light (10 nm to 400 nm) , visible light (400 nm to 700 nm) , infrared radiation (700 nm to 1.0 mm) , and microwave radiation (1 mm to 30 cm) .
  • the compounds of the invention inhibit PARP activity and, thus, are believed to be useful for treating neural tissue damage, particularly damage resulting from cerebral ischemia and reperfusion injury or neurodegenerative diseases in animals.
  • neural tissue refers to the various components that make up the nervous system including, without limitation, neurons, neural support cells, giia, Schwann cells, vasculature contained within and supplying these structures, the central nervous system, the brain, the brain stem, the spinal cord, the junction of the central nervous system with the peripheral nervous system, the peripheral nervous system, and allied structures .
  • an effective therapeutic amount of the compounds and compositions described above are administered to animals to effect a neuronal activity, particularly one that is not mediated by NMDA- receptor mediated neurotoxicity.
  • Such neuronal activity may consist of stimulation of damaged neurons, promotion of neuronal regeneration, prevention cf neurodegeneration and treatment of a neurological disorder.
  • the present invention further relates to a method of effecting a neuronal activity in an animal, comprising administering an eff ctive amount of the compound cf formula I to said animal .
  • neurological disorders examples include, withcut limitation, trigeminal neuralgia; glcssopharyngeal neuralgia; Eeli ' s Palsy; myasthenia gravis,- muscular dystrophy; amyotrophic lateral sclerosis,- progressive muscular atrophy,- progressive bulbar inherited muscular atrophy; herniated, ruptured or prolapsed invertebrate disk syndromes; cervical spondylosis ,- plexus disorders; thoracic cutlet destruction syndromes; peripheral neuropathies such as those caused by lead, dap ⁇ one, ticks, porphyna, er Guilla -Barre syndrome; Alzheimer's disease; Huntington's Disease and Parkinson's disease.
  • the term "neurodegenerative diseases” includes Alzheimer's disease, Parkinson's disease and Huntington's disease .
  • nervous insult refers to any damage to nervous tissue and any disability or death resulting therefrom.
  • the cause of nervous insult may be metabolic, toxic, neurotoxic, iatrogenic, thermal or chemical, and includes without limitation, ischemia, hypoxia, cerebrovascular accident, trauma, surgery, pressure, mass effect, hemmorrhage , radiation, vasospasm, neurodegenerative disease, infection,
  • Parkinson's disease amyotrophic lateral sclerosis (ALS) , myelination/demyelination process, epilepsy, cognitive disorder, glutamate abnormality and secondary effects thereof.
  • ALS amyotrophic lateral sclerosis
  • neuroprotective refers to the effect cf reducing, , arresting or ameliorating nervous insult, and projecting, resuscitating, or reviving nervous tissue that has suffered nervous insult.
  • preventing neurodegeneration includes the ability to prevent neurodegeneration in patients diagnosed as having a neurodegenerative disease or who are at risk of developing a neurodegenerative disease. The term also encompasses preventing further neurodegeneration in patients who are already suffering from or have symptoms of a neurodegenerative disease.
  • treating refers to:
  • the method of the present invention is particularly useful for treating a neurological disorder selected from the group consisting of: peripheral neuropathy caused by physical injury or disease state; head trauma, such as traumatic brain injury,-, physical damage to the spinal cord; stroke associated with brain damage, such as vascular stroke associated with hypoxia and brain damage, focal cerebral ischemia, global cerebral ischemia, and cerebral reperfusion injury; demyeiinating diseases, such as multiple sclerosis; and neurological disorders related to neurodegeneration, such as Alzheimer ' s Disease, Parkinson ' s Disease, Huntington ' s Disease and amyotrophic lateral sclerosis (ALS) .
  • a neurological disorder selected from the group consisting of: peripheral neuropathy caused by physical injury or disease state; head trauma, such as traumatic brain injury,-, physical damage to the spinal cord; stroke associated with brain damage, such as vascular stroke associated with hypoxia and brain damage, focal cerebral ischemia, global cerebral ischemia, and cerebral reperfusion injury; demyeiinating diseases, such as multiple sclerosis; and neurological disorders
  • neural tissue damage resulting from ischemia and reperfusion injury and neurodegenerative diseases includes neurotoxicity, such as seen in vascular stroke and global and focal ischemia.
  • the compounds, compositions and methods of the present invention are particularly useful for treating or preventing tissue damage resulting from cell death or damage due to necrosis or apoptosis.
  • cardiovascular disorders refers to those disorders that can either cause ischemia or are caused by reperfusion of the heart. Examples include, but are not limited to, coronary artery disease, angina ectoris, myocardial infarction, cardiovascular tissue damage caused by cardiac arrest, cardiovascular tissue damage caused by cardiac bypass, cardiogenic shock, and related conditions that would be known by those of ordinary skill in the art or which involve dysfunction of or tissue damage to the heart or vasculature, especially, but not limited to, tissue damage related to PARP activation.
  • the methods of the invention are believed to be useful for treating cardiac tissue damage, particularly damage resulting from cardiac ischemia or caused by reperfusion injury in animals.
  • the methods of the invention are particularly useful for treating cardiovascular disorders selected from the group consisting of: coronary artery disease, such as atherosclerosis; angina pectoris; myocardial infarction; myocardial ischemia and cardiac arrest; cardiac bypass; and cardiogenic shock.
  • the methods of the invention are particularly helpful in treating the acute forms of the above cardiovascular disorders .
  • the methods of the invention can be used to treat tissue damage resulting from cell damage or death due to necrosis or apoptosis, neural tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases,- to prevent or treat vascular stroke; to treat cr prevent cardiovascular disorders; to treat other conditions and/or disorders such as age-related macular degeneration, AIDS and other immune diseases, arthritis, atherosclerosis, cachexia, cancer, degenerative diseases of skeletal muscle involving replicative senescence, diabetes, head trauma, immune senescence, inflammatory bowel disorders (such as colitis and Crohn's disease), muscular dystrophy, osteoarthritis , osteoporosis, chronic and/or acute pain (such as neuropathic pain), renal failure, retinal ischemia, septic shock (such as endotoxic shock) , and skin aging; to extend the lifespan and proliferative capacity of cells; to alter gene expression of senescent cells; or to radiosensitize tumor cells
  • the methods of the invention can be used to treat cancer and to radiosensitize tumor cells.
  • cancer is interpreted broadly.
  • the compounds of the present invention can be "anti-cancer agents”, which term also encompasses “anti- tumor cell growth agents” and "anti- neoplastic agents”.
  • the methods of the invention are useful for treating cancers and radiosensitizing tumor cells in cancers such as ACTH-producing tumors, acute lymphocytic leukemia, acute nonl mphocytic leukemia, cancer of the adrenal cortex, bladder cancer, brain cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, esophageal cancer, Ewing ' s sarcoma, gallbladder cancer, hairy cell leukemia, head & neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer (small and/or non-small cell), malignant peritoneal effusion, malignant pleural effusion, melanoma, mesothelioma, multiple myeloma, neurobiastoma, non- Hodgkin ' s lymphom
  • radiosensitizer is defined as a molecule, preferably a low molecular weight molecule, administered to animals in therapeutically effective amounts to increase the sensitivity cf the cells to be radiosensitized to electromagnetic radiation and/or to promote the treatment of diseases which are treatable with electromagnetic radiation.
  • Diseases which are treatable with electromagnetic radiation include neopiastic diseases, benign and malignant tumors, and cancerous ceils. Electromagnetic radiation treatment of other diseases not listed herein are also contemplated by the present invention.
  • electromagnetic radiation and “radiation” as used herein includes, but is not limited to, radiation having the wavelength of 10 "20 to 10° meters.
  • Preferred embodiments of the present invention employ the electromagnetic radiation of: gamma-radiation (10 "2 ° to 10 “ “ ' m) x-ray radiation (10 _il to 10 “9 m) , ultraviolet light (10 nm to 400 nm) , visible light (400 nm to 700 nm) , infrared radiation (700 nm to 1.0 mm), and microwave radiation (1 mm to 30 cm) .
  • Radiosensitizers are known to increase the sensitivity of cancerous cells to the toxic effects of electromagnetic radiation.
  • hypoxic ceil radiosensitizers e.g., 2-nitro- imidazole compounds, and benzotriazine dioxide compounds
  • - non-hypoxic cell radiosensitizers e.g., halogenated pyri idines
  • various ether potential mechanisms of action have been hypothesized for radiosensitizers in the treatment of disease .
  • radiosensitizers activated by the electromagnetic radiation of x-rays.
  • x-ray activated radiosensitizers include, but are not limited to, the following: metronidazole , misonidazole , desmethylmisonidazole , pimonidazole , etanidazoie, nimorazole, mitomycin C, RSU 1069, SR 4233, E09, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR) , 5- iododeoxyur i d i ne (IUdR) , bromodeoxycyt i d ine , fluorodeoxyuridine (FudR) , hydroxyurea, cisplatin, and therapeutically effective analogs and derivatives of the same.
  • metronidazole misonidazole
  • desmethylmisonidazole pimonidazole
  • Photodynamic therapy (PDT) of cancers employs visible light as the radiation activator of the sensitizing agent.
  • photodynamic radiosensitizers include the following,- but are not limited to: hematoporphyrin derivatives, Photofrin, benzoporphyrin derivatives, NPe6, tin etioporphyrin SnET2 , pheoborbide-a, bacteriochlorophyll-a, naohthalocvanines, phthalocyanines, zinc phthalocyanine, and therapeutically effective analogs and derivatives of the same.
  • Radiosensitizers may be administered in conjunction with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds which promote the incorporation of radiosensitizers to the target ceils; compounds which control the flow of therapeutics, nutrients, and/or oxygen to the target cells; chemotherapeutic agents which act on the tumor with or without additional radiation; or other therapeutically effective compounds for treating cancer or other disease.
  • radiosensitizers examples include, but are not limited to: 5- fluorouracil , leucovorin, 5 ' -amino-5 ' deoxythymidine, oxygen, carbogen, red ceil transfusions, perfluorocarbons (e.g., Fluosol-DA) , 2,3-DPG, BW12C, calcium channel blockers , pentoxyfylline, antiangiogenesis compounds, hydralazine, and L-BSO.
  • 5- fluorouracil leucovorin
  • 5 ' -amino-5 ' deoxythymidine oxygen
  • carbogen red ceil transfusions
  • perfluorocarbons e.g., Fluosol-DA
  • 2,3-DPG 2,3-DPG
  • BW12C calcium channel blockers
  • pentoxyfylline e.g., 2,3-DPG, BW12C
  • antiangiogenesis compounds e.g., hydralazine, and
  • chemotherapeutic agents that may be used in conjunction with radiosensitizers include, but are not limited to: adriamycin, camptothecin, carboplatin, cisplatin, daunorubicin, docetaxei, ccxcrubicin, interferon (alpha, beta, gamma), interleukin 2, irinctecan, paclitaxel, topotecan, and therapeutically effective analogs and derivatives of the same.
  • the compounds of the present invention may also be used for radiosensitizing tumor ceils.
  • treating refers to: (i) preventing a disease, disorder or condition from occurring in an animal that may be predisposed to the disease, disorder and/or condition, but has not yet been diagnosed as having it;
  • compositions of the Invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising (i) a therapeutically effective amount of the compound of formula I and (ii) a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier refers to any carrier, diluent, excipient , suspending agent, lubricating agent, adjuvant, vehicle, delivery system, emulsifier, disintegrant , absorbent, preservative, surfactant, colorant, flavorant, or sweetener.
  • composition of the invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, intraventricularly, via an implanted reservoir in dosage formulations containing conventional ncn-toxic pharmaceutically-acceptable carriers, or by any other convenient dosage form.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraperitoneal , intrathecal , intraventricular, intrasternal , and intracranial injection or infusion techniques.
  • composition When administered parenterally, the composition will normally be in a unit dosage, sterile injectable form
  • sterile injectable forms are sterile injectable aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable forms may also be sterile injectable solutions or suspensions in non-toxic parenterally-acceptabie diluents or solvents, for example, as solutions in 1 , 3 -butanediol .
  • acceptable vehicles and solvents that may be employed are water, saline,
  • any bland fixed oil may be employed including synthetic mono- or di-giyc ⁇ rides , corn, cottonseed, peanut, and sesame oil.
  • Fatty acids such as ethyl oleate, isopropyl myristate, and oieic acid and its giyceride derivatives, including olive oil and castor oil, especially in their polyoxyethylated versions, are useful in the preparation of injectables.
  • These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants .
  • Sterile saline is a preferred carrier, and the compounds are often sufficiently water soluble to be made up as a solution for all foreseeable needs.
  • the carrier may contain miner amounts of additives, such as substances that enhance solubility, isotonicity, and chemical stability, e.g., anti- oxidants , buffers and preservatives.
  • additives such as substances that enhance solubility, isotonicity, and chemical stability, e.g., anti- oxidants , buffers and preservatives.
  • formulations for human medical use of the present invention comprise an active ingredient in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredient (s) .
  • the composition When administered orally, the composition will usually be formulated into unit dosage forms such as tablets, cachets, powder, granules, beads, chewabie lozenges, capsules, liquids, aqueous suspensions or solutions, or similar dosage forms, using conventional equipment and techniques known in the art .
  • Such formulations typically include a solid, semisolid, or liquid carrier.
  • Exemplary carriers include lactose, dextrose, sucrose, sorbitol, mannitoi, starches, gum acacia, calcium phosphate, mineral oil, cocoa butter, oil of theobrcma, alginates, tragacanth, gelatin, syrup, methyl cellulose, polyoxyethylene sorbitan monoiaurate, methyl hydroxybenzoate , propyl hydroxybenzoate, talc, magnesium stearate, and the like .
  • the composition of the invention is preferably administered as a capsule or tablet containing a single or divided dose of the inhibitor.
  • the composition is administered as a sterile solution, suspension, or emulsion, in a single or divided dose.
  • Tablets may contain carriers such as lactose and corn starch, and/or lubricating agents such as magnesium stearate.
  • Capsules may contain diluents including lactose and dried corn starch.
  • a tablet may be made by compressing or molding the active ingredient optionally with one or more accessory ingredients .
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free -flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active, cr dispersing agent.
  • Molded tablets may be made by molding in a suitable machine, a mixture of the powdered active ingredient and a suitable carrier moistened with an inert liquid diluent .
  • compositions of this invention may also be administered rectally in the form of suppositories.
  • These compositions can be prepared by mixing the drug with a suitable non- irritating excipient which is solid at room temperature, but liquid at rectal temperature, and, therefore, will melt in the rectum to release the drug.
  • suitable non- irritating excipient include cocoa butter, beeswax, and polyethylene giycols .
  • Compositions and methods of the invention also may utilize controlled release technology.
  • the inventive compounds may be incorporated into a hydrophobic polymer matrix for controlled release over a period of days.
  • composition of the invention may then be molded into a solid implant suitable for providing efficacious concentrations of the PARP inhibitors over a prolonged period of time without the need for frequent re-dosing.
  • controlled release films are well known to the art.
  • Particularly preferred are transdermal delivery systems.
  • Other examples of polymers commonly employed for this purpose that may be used in the present invention include nondegradable ethylene-vinyl acetate copolymer an degradable lactic acid-glycolic acid copolymers which may be used externally or internally.
  • Certain hydrogels such as poly (hydroxyethylmethacrylate) cr poly (vinylalcohol) also may be useful, but for shorter release cycles than the other polymer release systems, such as those mentioned above.
  • the carrier is a solid biodegradable polymer or mixture of biodegradable polymers with appropriate time release characteristics and release kinetics.
  • the composition of the invention may then be molded into a solid implant suitable for providing efficacious concentrations of the compounds of the invention over a prolonged period of time without the need for frequent re- dosing.
  • the composition of the present invention can be incorporated into the biodegradable polymer or polymer mixture in any suitable manner known to one of ordinary skill in the art and may form a homogeneous matrix with the biodegradable polymer, or may be encapsulated in some way within the polymer, or may be molded into a solid implant.
  • the biodegradable polymer or polymer mixture is used to form a soft "depot" containing the pharmaceutical composition of the present invention that can be administered as a flowable liquid, for example, by injection, but which remains sufficiently viscous to maintain the pharmaceutical composition within the localized area around the injection site.
  • the degradation time cf the depot so formed can be varied from several days to a few years, depending upon the polymer selected and its molecular weight.
  • a polymer composition in injectable form even the need to make an incision may be eliminated.
  • a flexible or flcwable delivery "depot” will adjust to the shape of the . space it occupies with the body with a minimum of trauma to surrounding tissues.
  • the pharmaceutical composition of the present invention is used in amounts that are therapeutically effective, and may depend upon the desired release profile, the concentration of the pharmaceutical composition required for the sensitizing effect, and the length of time that the pharmaceutical composition has to be released for treatment .
  • the PARP inhibitors are used in the composition in amounts that are therapeutically effective.
  • Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, welling, or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • Said compositions are prepared according to conventional mixing, granulating, or coating methods, and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient.
  • the compounds of the present invention should readily penetrate the blood-brain barrier when peripherally administered.
  • Compounds which cannot penetrate the blood- brain barrier can be effectively administered by an intraventricular route or other appropriate delivery system suitable for administration to the brain.
  • Doses of the compounds preferably include pharmaceutical dosage units comprising an efficacious quantity of active compound.
  • an efficacious quantity is meant a quantity sufficient to inhibit PARP and derive the beneficial effects therefrom through administration of one or more of the pharmaceutical dosage units.
  • the dose is sufficient to prevent or reduce the effects of vascular stroke or ether neurodegenerative diseases .
  • the amount required of the active ingredient to achieve a therapeutic effect will vary with the particular compound, the route of administration, the mammal under treatment, and the particular disorder or disease being treated.
  • a suitable systematic dose of a compound of the present invention or a pharmacologically acceptable salt thereof for a mammal suffering from, or likely to suffer from, any of condition as described hereinbefore is in the range of about 0.01 mg/kg to about 100 mg/kg of the active ingredient compound, the most preferred dosage being about 0.1 to about 10 mg/kg.
  • a specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the molecular weight of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the severity of the particular disease being treated and form of administration .
  • the compounds may also be blended with conventional excipients such as binders, including gelatin, pregelatinized starch, and the like; lubricants, such as hydrogenated vegetable cii, stearic acid, and the like; diluents, such as lactose, mannose, and sucrose; disintegrants, such as carboxymethylcellulose and sodium starch glycolate; suspending agents, such as povidone, polyvinyl alcohol, and the like; absorbants, such as silicon dioxide; preservatives, such as methylparaben, propylparaben, and sodium benzoate,- surfactants, such as sodium iauryl sulfate, polysorbate 80, and the like; colorants such as F.D.& C. dyes and lakes; flavorants; and sweeteners.
  • binders including gelatin, pregelatinized starch, and the like
  • lubricants such as hydrogenated vegetable cii, stearic acid, and the like
  • diluents such
  • the present invention relates to the use of the compounds of formula I in the preparation of a medicament for the treatment of any disease cr disorder in an animal described herein.
  • a convenient method to determine IC 50 of a PARP inhibitor compound is a PARP assay using purified recombinant human PARP from Trevigan (Gaithersburg, MD) , as follows: The PARP enzyme assay is set up on ice in a volume of 100 microliters consisting of 100 mM Tris-KCi (pH 8.0) , 1 mM MgCl 2 , 28 mM KC1 , 28 mM NaCl, 0.1 mg/ml of herring sperm DNA (activated as a 1 mg/ml stock for 10 minutes in a 0.15% hydrogen peroxide solution), 3.0 micromciar [3H] nicotinamide adenine dinucleotide (470 mci/mmole ' , 7 micrograms/ml PARP enzyme, and various concentrations of the compounds to be tested.
  • the PARP enzyme assay is set up on ice in a volume of 100 microliters consisting of 100 mM Tris-
  • the reaction is initiated by incubating the mixture at 25°C. After 15 minutes of incubation, the reaction is terminated by adding 500 microliters of ice cold 20% (w/v) trichloroacetic acid. The precipitate formed is transferred onto a glass fiber filte (Packard Unifilter-GF/B) and washed three times with ethanol . After the filter is dried, the radioactivity is determined by scintillation counting.
  • the compounds of this invention were found to have potent enzymatic activity in the range of a few nM to 20 M in IC S0 in this inhibition assay.
  • Focal cerebral ischemia experiments were performed using male Wistar rats weighing 250-300 g which were anesthetized with 4% halothane. This anesthesia was maintained with 1.0- 1.5% haiothane until the end of the surgery. The animals were placed in a warm environment to avoid a decrease of body temperature during surgery. An anterior midline cervical incision was made. The right common carotid artery (CCA) was exposed and was isolated from the vagus nerve. A silk suture was placed and tied around the CCA in proximity to the heart. The external carotid artery (ECA) was then exposed and was ligated with a silk suture .
  • CCA right common carotid artery
  • ECA external carotid artery
  • the catheter was tied in place with a silk suture. Then, a 4-0 nylon suture (Braun Medical, Crissier, Switzerland) was introduced into the catheter lumen and was pushed until the tip blocked the anterior cerebral artery.
  • the brains were immediately removed, frozen on dry ice and stored at -80°C.
  • the brains were then cut in 0.02 mm-thick sections in a cryocut at -19°C, taking one of every 20 sections.
  • the sections were stained with cresyl violet according to the Nissl procedure.
  • Each section was examined under a light microscope and the regional infarct area was determined according to the presence of cells with morphological changes.
  • Various doses of compounds were tested in this model .
  • the compounds were given in either single or multiple doses, i.p. or i.v., at different times before or after the onset of ischemia.
  • Compounds of this invention were found to have protection in the range of 20 to 80 per cent in this assay.
  • the experiments of the heart ischemia/reperfusion injury model were performed using female Sprague-Dawley rats weighing 300-350g which were anesthetized with intraperitoneal ketamine at a dose of 150 mg/kg.
  • the rats were endotracheally incubated and ventilated with oxygen-enriched room air using a Harvard rodent ventilator.
  • Polyethylene catheters inserted into the carotid artery and the femoral vein were used for artery blood pressure monitoring and fluid administration, respectively.
  • Arterial pC0 2 was maintained between 35 and 45 mm Hg by adjusting the respiratory rate.
  • the rat chests were opened by median sternotomy, the pericardium was incised, and the hearts were cradled with a latex membrane tent .
  • Hemcdynamic data were obtained at baseline after at least 15 minute stabilization from the end cf the surgical operation.
  • the LAD (left anterior descending) coronary artery was ligated for 40 minutes and was followed by 120 minutes of reperfusion. After 120 minutes of reperfusion, the LAD artery was reoccluded, and a 0.1 ml bolus of monastral blue dye was injected into the left atrium to determine the ischemic risk region.
  • the hearts were then arrested with potassium chloride. The hearts were cut into five 2-3 mm thick transverse slices, and each slice was weighed. The sections were incubated in a 1% solution of triphenyitetrazolium chloride to visualize the infarcted myocardium located within the risk region.
  • Infarct size was calculated by summing the values for each left ventricular slice and expressed as a fraction of the risk region of the left ventricle.
  • Various doses of compounds were tested in this model .
  • the compounds were given, in either single or multiple doses, i.p or i.v., at different times before or after the onset of ischemia.
  • the compounds of this invention were found to have ischemia/reperfusion injury protection in the range of 10 to 40 percent in this assay.
  • the compounds of this invention protect against ischemia- induced degeneration of rat hippocampai neurons in vitro and thus may be useful in disorders arising from cerebral ischemia such as stroke, septic shock, or CNS degenerative disorders.
  • the present invention is further directed to a method of prophylactic or therapeutic treatment of heart attack, cardiac arrest, cardiac bypass, diabetes, or risk cf damage which comprises administering an effective amount of a compound cf the present invention for PARP inhibition in unit dosage form.
  • Example 2 To a stirred solution of the corresponding R-COOH (0.001 M) and Et 3 N (0.00130 M) in dry THF (20 ml) was added ethyl chloroformate (0.00125 M) dropwise for 5-7 minutes at room temperature. After 30 Minutes of stirring at room temperature, Indoine Blue (0.5 g, 0.001 M) in THF was added dropwise for 30 minutes at room temperature, and the formed mixture was stirred at room temperature for 18 hours. The mixture was poured on ice-water (200 g) and stirred for an additional 0.5 hours. The solid product formed was collected by filtration and recrystallized from a DMA/H 2 0 mixture.
  • R can be any possible substituent as described herein, including :
  • the IC 50 of with respect to PARP inhibition was determined for several compounds by a PARP assay using purified recombinant human PARP from Trevigen (Gaithersburg, MD) , as follows : The PARP enzyme assay was set up on ice in a volume of 100 microliters consisting of 10 mM Tris-HCl (pH 8.0) , 1 mM
  • the compounds have an IC 5 0 for inhibiting poly(ADP-ribose) synthase in vitro of preferably 50 ⁇ M or lower, more preferably 25 ⁇ M or lower, and most preferably lO ⁇ M or lower. Similar IC 50 values can be obtained for the other disclosed phenazine compounds of the invention.
  • Focal cerebral ischemia was produced by cauterization of the right distal MCA (middle cerebral artery) with bilateral temporary common carotid artery occlusion in male Long-Evans rats for 90 minutes. All procedures performed on the animals were approved by the University Institutional Animal Care and Use Committee of the University of Pennsylvania. A total of 42 rats (weights: 230-340 g) obtained from Charles River were used in this study. The animals fasted overnight with free access to water prior to the surgical procedure.
  • DMSC dimethyl sulfoxide
  • the rats were then anesthetized with halothane (4% for induction and 0.8%-I.2% for the surgical procedure) in a mixture of 70% nitrous oxide and 30% oxygen.
  • the body temperature was monitored by a rectal probe and maintained at
  • the head of the animal was positioned in a stereotaxic frame, and a right parietal incision between the right lateral canthus and the external auditory meatus was made.
  • a dental drill constantly cooled with saline, a 3 mm burr hole was prepared over the cortex supplied by the right MCA, 4 mm lateral to the sagittal suture and 5 mm caudal to the coronal suture.
  • the dura mater and a thin inner bone layer were kept, care being taken to position the probe over a tissue area devoid of large blood vessels.
  • the flow probe (tip diameter of 1 mm, fiber separation of 0.25 mm) was lowered to the bottom of the cranial burr hole using a micromanipulator .
  • the probe was held stationary by a probe holder secured to the skull with dental cement.
  • the microvascular blood flow in the right parietal cortex was continuously monitored with a laser Doppler flowmeter (FloLab, Moor, Devon, U.K., and Periflux 4001, Perimed, Sweden).
  • Focal cerebral ischemia was produced by cauterization of the distal portion of the right MCA with bilateral temporary common carotid artery (CCA) occlusion by the procedure of Chen et al . , "A Model of Focal Ischemic Stroke in the Rat: Reproducible Extensive Cortical Infarction", Stroke 17:738-43 (1986) and/cr Liu et al .
  • bilateral CCA's were isolated, and loops made from polyethylene (PE-10) catheter were carefully passed around the CCA's for later remote occlusion.
  • the incision made previously for placement of the laser doppler probe was extended to allow observation of the rostral end of the zygomatic arch at the fusion point using a dental drill, and the dura mater overlying the MCA was cut.
  • the MCA distal to its crossing with the inferior cerebral vein was lifted by a fine stainless steel hook attached to a micromanipulator and, following bilateral CCA occlusion, the MCA was cauterized with an el ⁇ ctrocoaguiator .
  • the burr hole was covered with a small piece of Gelform, and the wound was sutured to maintain the brain temperature within the normal cr near-normal range.
  • mice Twenty- four hours after MCA occlusion, the rats were sacrificed with an intraperitoneal injection of pentobarbital sodium (150 mg/kg) .
  • the brain was carefully removed from the skull and cooled in ice-cold artificial CSF for five minutes.
  • the cooled brain was then sectioned in the coronal plane at 2 mm intervals using a rodent brain matrix (RBM-4000C, ASI Instruments, Warren, Michigan).
  • the brain slices were incubated in phosphate-buff red saline containing 2% 2,3,5- triphenyltetrazolium chloride (TTC) at 37°C for ten minutes.
  • TTC 2,3,5- triphenyltetrazolium chloride
  • the data are expressed as mean ⁇ standard deviation. The significance of differences between groups was determined using an analysis of variance (ANOVA) followed by Student's t- test for individual comparisons .
  • MABP mean arterial blood pressure
  • Focal cerebral ischemia experiments are performed using male Wistar rats weighing 250 - 300 g, which are anesthetized with 4% halothane . Anesthesia is maintained with 1.0-1.5% halothane until the end of surgery. The animals are installed in a warm environment to avoid a decrease in body temperature during surgery.
  • the right common carotid artery (CCA) is exposed and isolated from the vagus nerve.
  • a silk suture is placed and tied around the CCA in proximity to the heart.
  • the external carotid artery (ECA) is then exposed and ligated with a silk suture.
  • a puncture is made in the CCA and a small catheter (PE 10, Ulrich & Co., St-Gallen, Switzerland) is gently advanced to the lumen of the internal carotid artery (ICA) .
  • ICA internal carotid artery
  • the catheter is tied in place with a silk suture.
  • a 4-0 nylon suture (Braun Medical, Crissier, Switzerland) is introduced into the catheter lumen and is pushed until the tip blocks the anterior cerebral artery.
  • the length of catheter into the ICA is approximately 19 mm from the origin of the ECA.
  • the suture is maintained in this position by occlusion of the catheter with heat .
  • One cm of catheter and nylon suture are left protruding so that the suture can be withdrawn to allow reperfusion.
  • the skin incision is then closed with wound clips.
  • the animals are maintained in a warm environment during recovery from anesthesia. Two hours later, the animals are re-anesthetized, the clips are discarded, and the wound is re-opened.
  • the catheter is cut, and the suture is pulled out.
  • the catheter is then obturated again by heat, and wound clips are placed on the wound.
  • the animals are allowed to survive for 24 hours with free access to food and water.
  • the ra t s are then sacrificed with C0 2 and
  • the brains are immediately removed, frozen on dry ice and stored at -80°C.
  • the brains are then cut in 0.02 mm-thick sections in a cryocut at -19°C, selecting one of every 20 sections for further examination.
  • the selected sections are stained with cre ⁇ yl violet according to the Nissl procedure. Each stained section is examined under a light microscope, and the regional infarct area is determined according to the presence of cells with morphological changes.
  • Various doses of the compounds of the invention are tested in this model.
  • the compounds are administered in either a single dose cr a series of multiple doses, i.p. or i.v., at different times, both before or after the onset of ischemia.
  • Compounds of the invention are found to provide protection from ischemia in the range of about 20 to 80%.
  • the rats are endotracheally intubat ⁇ d and ventilated with oxygen-enriched room air using a Harvard rodent ventilator.
  • Polyethylene catheters inserted into the carotid artery and the femoral vein are used for artery blood pressure monitoring and fluid administration respectively.
  • Arterial pC0 2 is maintained between 35 and 45mm Hg by adjusting the respirator rate.
  • the rat chests are opened by median sternotomy, the pericardium is incised, and the hearts are cradled with a latex membrane tent . Hemodynamic data are obtained at baseline after at least a 15-minute stabilization period following the end of the surgical operation.
  • the LAD left atrium
  • ischemic risk region (left anterior descending) coronary artery is ligated for 40 minutes, and then re-perfused for 120 minutes. After 120 minutes' reperfusion, the LAD artery is re-occluded, and a 0.1 ml bolus of monastral blue dye is injected into the left atrium to determine the ischemic risk region.
  • the hearts are then arrested with potassium chloride and cut into five 2-3 mm thick transverse slices. Each slice is weighed and incubated in a 1% solution of trimethyltetrazolium chloride to visualize the infarcted myocardium located within the risk region. Infarct size is calculated by summing the values for each left ventricular slice and is further expressed as a fraction of the risk region cf the left ventricle .
  • the compounds of the invention are tested in this model .
  • the compounds are given either in a single dose or a series of multiple doses, i.p. or i.v., at different times, both before or after the onset of ischemia.
  • the compounds of the invention are found to have ischemia/reperfusion injury protection in the range of 10 to 40 percent. Therefore, they protect against ischemia-induced degeneration of rat hippocampal neurons in vitro.
  • a patient just diagnosed with acute retinal ischemia is immediately administered parenterally, either by intermittent or continuous intravenous administration, a compound of formula I, either as a single dose or a series of divided doses of the compound.
  • the patient optionally may receive the same or a different compound of the invention in the form of another parenteral dose. It is expected by the inventors that significant prevention of neural tissue damage would ensue and that the patient's neurological symptoms would considerably lessen due to the administration of the compound, leaving fewer residual neurological effects post-stroke. In addition, it is expected that .the re-occurrence of retinal ischemia would be prevented or reduced.
  • Example 9 Treatment of Retinal Ischemia
  • a patient has just been diagnosed with acute retinal ischemia.
  • a physician or a nurse parenterally administers a compound of formula I, either as a single dose or as a series of divided doses.
  • the patient also receives the same or a different PARP inhibitor by intermittent or continuous administration via implantation of a biocompatible, biodegradable polymeric matrix delivery system comprising a compound of formula I via a subdural pump inserted to administer the compound directly to the infarct area of the brain. It is expected by the inventors that the patient would awaken from the coma more quickly than if the compound of the invention were not administered.
  • the treatment is also expected to reduce the severity cf the patient's residual neurological symptoms. In addition, it is expected that re- occurrence of retinal ischemia would be reduced.
  • a patient just diagnosed with acute vascular stroke is immediately administered parenterally, either by intermittent or continuous intravenous administration, a compound of formula I, either as a single dose or a series of divided doses of the compound.
  • the patient optionally may receive the same or a different compound of the invention in the form of another parenteral dose. It is expected by the inventors that significant prevention of neural tissue damage would ensue and that the patient ' s neurological symptoms would considerably lessen due to the administration of the compound, leaving fewer residual neurological effects post-stroke. In addition, it is expected that the re-occurrence of vascular stroke would be prevented or reduced.
  • Example 11 Treatment of Vascular Stroke A pat ⁇ ent has just been diagnosed with acute multiple vascular strokes and is comatose. Immediately, a physician or a nurse parenterally administers a compound of formula I, either as a single dose or as a series of divided doses . Due to the comatose state of the patient, the patient also receives the same or a different PARP inhibitor by intermittent or continuous administration via implantation of a biocompatible, biodegradable polymeric matrix delivery system comprising a compound of formula I, or via a subdural pump inserted to administer the compound directly to the infarct area of the brain. It is expected by the inventors that the patient would awaken from the coma more quickly than if the compound of the invention were not administered. The treatment is also expected to reduce the severity of the patient's residual neurological symptoms. In addition, it is expected that re-occurrence of vascular stroke would be reduced.
  • Example 12 Preventing Cardiac Reperfusion Injury A patient is diagnosed with life-threatening cardiomyopathy and requires a heart transplant . Until a donor heart is found, the patient is maintained on Extra Corporeal Oxygenation Monitoring (ECMO) .
  • ECMO Extra Corporeal Oxygenation Monitoring
  • a donor heart is then located, and the patient undergoes a surgical transplant procedure, during which the patient is placed on a heart-lung pump.
  • the patient receives a compound of the invention intracardiac within a specified period of time prior to re-routing his or her circulation from the heart -lung pump to his or her new heart, thus preventing cardiac reperfusion injury as the new heart begins to beat independently of the external heart -lung pump.
  • mice weighing 18 to 20 g were administered a test compound, 1-carboxynaphthaiene-l- carboxamide at the doses of 60, 20, 6 and 2 mg/kg, daily, by intraperitoneai (IP) injection for three consecutive days.
  • IP intraperitoneai
  • Each animal was first challenged with lipopolysaccharide (LPS, from E. Coli, LD 100 of 20 mg/animal IV) plus galactosamine (20 mg/animal IV) .
  • LPS lipopolysaccharide
  • galactosamine (20 mg/animal IV
  • a patient has just been diagnosed with a disorder requiring the administration of a PARP inhibitor.
  • a physician or a nurse parenterally administers a compound of formula I, either as a single dose or as a series of divided doses.
  • the patient may receive the same or a different PARP inhibitor by intermittent or continuous administration via implantation of a biocompatible, biodegradable polymeric matrix delivery system comprising a compound of formula I, or via a subdural pump inserted to administer the compound directly to the desired treatment location. It would be expected that the treatment would alleviate the disorder, either in part or in its entirety and that no further occurrences of the disorder would develop.
  • Example 23 A treatment such as that described in Example 14 wherein the patient is diagnosed with a demyeiinating disease.
  • Example 29 A treatment such as that described in Example 14 wherein the patient is diagnosed with amyotrophic lateral sclerosis.
  • Example 30 A treatment such as that described in Example 14 wherein the patient is diagnosed with angina pectoris.
  • the human prostate cancer cell line, PC-3s were plated in 6 well dishes and grown at monolayer cultures RPMI1640 supplemented with 10% FCS .
  • the cells are maintained at 37°C in 5% C0 2 and 95% air.
  • the cells were exposed to a dose response (0.1 mM to 0.1 ⁇ M) of 3 different PARP mbitors of Formula I disclosed herein prior to irradiation at one sublethal dose level.
  • the six well plates were exposed at room temperature in a Seifert
  • a patient Before undergoing radiation therapy to treat cancer, a patient is administered an effective amount of a compound or a pharmaceutical composition cf the present invention.
  • the compound or pharmaceutical composition acts as a radiosensitizer and making the tumor more susceptible to radiation therapy.
  • Probes specific for senescence-related genes are analyzed, and treated and control cells compared. In analyzing the results, the lowest level of gene expression is arbitrarily set at 1 to provide a basis for comparison.
  • Three genes particularly relevant to age-related changes in the skin are collagen, collagenase and elastin. West, Arch . Derm . 130:87-95 (1994).
  • Elastin expression of the cells treated with the PARP inhibitor of Formula I is significantly increased in comparison with the control cells .
  • Elastin expression is significantly higher in young cells compared to senescent cells, and thus treatment with the PARP inhibitor of Formula I causes elastin expression levels in senescent cells to change to levels similar to those found in much younger cells.
  • a beneficial effect is seen in collagenase and ' collagen expression with treatment with the PARP inhibitors of Formula I.
  • Approximately 105 BJ cells, at PDL 95-100 are plated and grown in 15 cm dishes.
  • the growth medium is DMEM/199 supplemented with 10% bovine calf serum.
  • the cells are treated daily for 24 hours with the PARP inhibitors of Formula I (100 ⁇ g/ 1 mL of medium) .
  • the cells are washed with phosphate buffered solution (PBS) , then permeablized with 4% paraformaldehyde for 5 minutes, then washed with PBS, and treated with 100% cold methanol for 10 minutes.
  • the methanol is removed and the cells are washed with PBS, and then treated with 10% serum to block nonspecific antibody binding.
  • Vector is added to the cells and the mixture incubated for 1 hour.
  • the cells are rinsed and washed three times with PBS.
  • a secondary antibody, goat anti- mouse IgG (1 mL) with a biotin tag is added along with 1 mL of a solution containing streptavidin conjugated to alkaline phosphatase and 1 mL of NBT reagent (Vector) .
  • the cells are washed and changes in gene expression are noted colorimetrically .
  • human fibroblast cells lines (either W138 at Population
  • Doubling (PDL) 23 or BJ cells at PDL 71) are thawed and plated on T75 flasks and allowed to grow in normal medium (DMEM/M199 plus 10% bovine calf serum) for about a week, at which time the dells are confluent, and the cultures are therefor ready to be subdivided.
  • the media is aspirated, and the cells rinsed with phosphate buffer saline (PBS) and then trypsinized.
  • PBS phosphate buffer saline
  • the cells are counted with a Coulter counter and plated at a density of 10° cells per cm 2 in 6 -well tissue culture plates in DMEM/199 medium supplemented with 10% bovine calf serum and varying amounts (O.lO ⁇ M, and ImM: from a 100X stock solution in DMEM/M199 medium) of a PARP inhibitor of Formula I as disclosed herein. This process is repeated every 7 days until the ceil appear to stop dividing. The untreated (control) cells reach senescence and stop dividing after about 40 days in culture.
  • Treatment of cells with 10 ⁇ M 3 -AB appears to have little or no effect in contrast to treatment with 100 ⁇ M 3 -AB which appears lengthen the lifespan of the cells and treatment with 1 mM 3 -AB which dramatically increases the lifespan and proliferative capacity of the cells.
  • the cells treated with 1 mM 3-AB will still divide after 60 days in culture.
  • CCI Chronic Constriction Injury
  • Nerve ligation is performed by exposing one side of the rat's sciatic nerves and dissecting a 5-7 mm-long nerve segment and closing with four loose ligatures at a 1.0- 1.5-mm, followed by implanting of an intrathecal catheter and inserting of a gentamicin sulfate-flushed polyethylene (PE-10) tube into the subarachnoid space through an incision at the cisterna magna .
  • PE-10 gentamicin sulfate-flushed polyethylene
  • the caudal end of the catheter is gently threaded to the lumbar enlargement and the rostral end is secured with dental cement to a screw embedded in the skull and the skin wound is closed with wound clips.
  • Thermal hyperalgesia to radiant heat is assessed by using a paw-withdrawal test.
  • the rat is placed in a plastic cylinder on a 3 -mm thick glass plate with a radiant heat source from a projection bulb placed directly under the plantar surface of the rat's hindpaw.
  • the paw-withdrawal latency is defined as the time elapsed from the onset of radiant heat stimulation to withdrawal of the rat's hindpaw.
  • Mechanical hyperalgesia is assessed by placing the rat in a cage with a bottom made of perforated metal sheet with many small square holes. Duration of paw-withdrawal is recorded after pricking the mid-plantar surface of the rat's hindpaw with the tip of a safety pin inserted through the cage bottom.
  • Mechano-allodynia is assessed by placing a rat in a cage similar to the previous test, and applying von Frey filaments in ascending order of bending force ranging from 0.07 to 76 g to the mid-plantar surface of the rat's hindpaw.
  • a von Frey filament is applied perpendicular to the skin and depressed slowly until it bends.
  • a threshold force of response is defined as the first filament in the series to evoke at least one clear paw-withdrawal out of five applications.
  • Dark neurons are observed bilaterally within the spinal cord dorsal horn, particularly in laminae I -II, of rats 8 days after unilateral sciatic nerve ligation as compared with sham operated rats.
  • Various doses of differing compounds of Formula I tested in this model and show that the Formula I compounds reduce both incidence of dark neurons and neuropathic pain behavior in CCI rats .

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Abstract

L'invention se rapporte à des composés, à des compositions pharmaceutiques et à des méthodes d'utilisation de composés représentés par la formule (I), dans laquelle R1-R9 et Z sont indépendamment hydrogène, hydroxy, halo, haloalkyle, thiocarbonyle, cyano, nitro, amino, imino, alkylamino, aminoalkyle, sulfhydryle, thioalkyle, alkylthio, sulfonyle, alkylsulfonyle, alkyle à chaîne linéaire ou ramifiée C1-C9, alcényle à chaîne linéaire ou ramifiée C2-C9, alkynyle à chaîne linéaire ou ramifiée C2-C9, alcoxy à chaîne linéaire ou ramifiée C1-C6, alkenoxy à chaîne linéaire ou ramifiée C2-C6, alkynoxy à chaîne linéaire ou ramifiée C2-C6, aryle, carbocycle, hétérocycle, aralkyle, alkylaryle, alkylaryloxy, aryloxy, aralkyloxy, aralkylsulfonyle, aralkylamino, arylamino, arylazo, arylthio; ou Z est un composé représenté par la formule (II), dans laquelle U est C ou N, et R7 et R8 sont définis ci-dessus; et X et Y sont indépendamment aryle, carbocycle ou hétérocycle.
PCT/US1999/030979 1998-12-31 1999-12-28 Composes phenazine, methodes et compositions pharmaceutiques permettant d'inhiber la poly(adp-ribose) polymerase (parp) WO2000039104A1 (fr)

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